Patient acceptability, safety and access : A balancing act for selecting age-appropriate oral dosage forms for paediatric and geriatric populations

© 2017 Elsevier B.V. All rights reserved.The selection and design of age-appropriate formulations intended for use in paediatric and geriatric patients are dependent on multiple factors affecting patient acceptability, safety and access. The development of an economic and effective product relies on a balanced consideration of the risks and benefits of these factors. This review provides a comprehensive and up-to-date analysis of oral dosage forms considering key aspects of formulation design including dosage considerations, ease of use, tolerability and safety, manufacturing complexity, stability, supply and cost. Patient acceptability has been examined utilising an evidence-based approach to evaluate regulatory guidance and literature. Safety considerations including excipients and potential risk of administration errors of the different dosage forms are also discussed, together with possible manufacturing and supply challenges. Age appropriate drug product design should consider and compare i) acceptability ii) safety and iii) access, although it is important to recognise that these factors must be balanced against each other, and in some situations a compromise may need to be reached when selecting an age-appropriate formulation.Peer reviewedFinal Accepted Versio

Patient-centred pharmaceutical design to improve acceptability of medicines : similarities and differences in paediatric and geriatric populations

Open Access. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.Patient acceptability of a medicinal product is a key aspect in the development and prescribing of medicines. Children and older adults differ in many aspects from the other age subsets of population and require particular considerations in medication acceptability. This review highlights the similarities and differences in these two age groups in relation to factors affecting acceptability of medicines. New and conventional formulations of medicines are considered regarding their appropriateness for use in children and older people. Aspects of a formulation that impact acceptability in these patient groups are discussed, including, for example, taste/smell/viscosity of a liquid and size/shape of a tablet. A better understanding of the acceptability of existing formulations highlights opportunities for the development of new and more acceptable medicines and facilitates safe and effective prescribing for the young and older populationsPeer reviewedFinal Published versio

Understanding Conformational Regulation of the Integrin I-domain for Design of Chimeric Protein Switches

Within all complex biological processes intricate proteins are expressed to complete every niche and necessary task. Many express multiple allosterically regulated conformational states, with protein function regulated by effector molecules and other ligands. One such protein is the LFA-1 surface integrin protein and its inserted domain, the I-domain. We Isolated the I-domain for investigation of determining binding properties and understanding conformational regulations of affinity changes to its target ligand ICAM-1, for further use in chimeric protein switch design. A large change in binding affinity was found through the deletion of a sub-sequence of amino acids in I-domain known as the α7 helix. Our investigation shows that, when the α7 helix is deleted, I-domain converts into a permanent high affinity state in which binding affinity to ICAM-1 was increased, and this state can be reversed by co-expression with soluble α7 helix peptide. These results conclude that the α7 helix stabilizes the I domain in its low affinity conformation in a ligand-like manner, allowing relaxation to the high affinity conformation upon disruption of α7 helix interaction. While deletion of the α7 helix yields higher binding affinity in I-domain it cannot be applied in design of chimeric protein switches due to its permanent conformational state. Because of this, our switch design has a focus of allosterically regulating the I-domain and α7 helix through utilizing on/off switching of conformational states. I-domain is fused with EF3 and EF4 hands of calmodulin, which then regulates binding affinity to ICAM-1 through interaction with α7 helix, when the EF hands’ natural ligand peptides are present. Currently, mutant switches are being developed to alter EF hand binding specificity which, when bound to new target ligands, will cause an increase in I-domain-ICAM-1 binding affinity in switch molecules. The results of these allosteric regulations highlight the potential of chimeric protein switches for design of environmentally responsive targeting agents and suggest that, through directed evolution, regulated binding to a range of novel targets could be achieved for therapeutic intervention

Notch Simultaneously Orchestrates Multiple Helper T Cell Programs Independently of Cytokine Signals

SummaryTwo models are proposed to explain Notch function during helper T (Th) cell differentiation. One argues that Notch instructs one Th cell fate over the other, whereas the other posits that Notch function is dictated by cytokines. Here we provide a detailed mechanistic study investigating the role of Notch in orchestrating Th cell differentiation. Notch neither instructed Th cell differentiation nor did cytokines direct Notch activity, but instead, Notch simultaneously regulated the Th1, Th2, and Th17 cell genetic programs independently of cytokine signals. In addition to regulating these programs in both polarized and nonpolarized Th cells, we identified Ifng as a direct Notch target. Notch bound the Ifng CNS-22 enhancer, where it synergized with Tbet at the promoter. Thus, Notch acts as an unbiased amplifier of Th cell differentiation. Our data provide a paradigm for Notch in hematopoiesis, with Notch simultaneously orchestrating multiple lineage programs, rather than restricting alternate outcomes

Seamless pedestrian positioning and navigation using landmarks

Many navigation services, such as car navigation services, provide users with praxic navigational instructions (such as “turn left after 200 metres, then turn right after 150 metres”), however people usually associate directions with visual cues (e.g. “turn right at the square”) when giving navigational instructions in their daily conversations. Landmarks can play an equally important role in navigation and routing services. Landmarks are unique and easy-to-recognise and remember features; therefore, in order to remember when exploring an unfamiliar environment, they would be assets. In addition, Landmarks can be found both indoors and outdoors and their locations are usually fixed. Any positioning techniques which use landmarks as reference points can potentially provide seamless (indoor and outdoor) positioning solutions. For example, users can be localised with respect to landmarks if they can take a photograph of a registered landmark and use an application for image processing and feature extraction to identify the landmark and its location. Landmarks can also be used in pedestrian-specific path finding services. Landmarks can be considered as an important parameter in a path finding algorithm to calculate a route passing more landmarks (to make the user visit a more tourist-focussed area, pass along an easier-to-follow route, etc.). Landmarks can also be used as a part of the navigational instructions provided to users; a landmark-based navigation service makes users sure that they are on the correct route, as the user is reassured by seeing the landmark whose information/picture has just been provided as a part of navigational instruction. This paper shows how landmarks can help improve positioning and praxic navigational instructions in all these ways

Bacteria-mediated reactivation of gammaherpesviruses

Significant morbidity is associated with the synergistic and inhibitory interactions of bacteria, viruses, parasites, and fungi. The oral cavity, gut, and genitourinary tract are home to many of these organisms and are the site of virus-associated malignancies that affect millions worldwide. Yet little is known with regard to the cellular and molecular interactions of viral pathogens with the normal flora as well as the interactions among pathogens themselves. Our laboratory is interested in understanding the role of factors present within the immediate environment that may influence reactivation of persistent infection and pathogenesis. Our central hypothesis is that viral-bacterial interactions foster enhanced pathogen replication and modulation of the immune response in the mouth, GI tract, and genito-urinary tract. The detection of replicating virus in these tissues has incited investigation into the relationship between bacterial infection and herpesviral reactivation. We hypothesized that bacterial end-products including short chain fatty acids (SCFA), lipopolysaccharide (LPS), and lipoteichoic acid (LTA) secreted by oral bacteria initiate viral reactivation from latency. Latently infected EBV, KSHV, and MHV 68 cell lines were incubated with crude spent media containing secreted SCFA, and components of bacterial pathogens (E. faecalis, Bacteriodes, Prevotella, Porphomonas, and Fusiobacterium Nucleatum). Cells were then assayed for viral promoter activation, promoter-protein interactions, and state of infection. Following incubation with crude spent media, viral immediate early promoters were activated, the viral early genes were upregulated as determined by RT PCR and western blot, and linear genomes were detected. HDAC inhibition activity as well as protein kinase C activity increased significantly following treatment with bacterial spent media. KSHV and EBV were consistently reactivated by bacterial metabolites but the mechanism of reactivation was both bacteria, virus, and cell type specific. Interestingly, EBV was preferentially reactivated following toll like receptor stimulation while KSHV and HSV-1 reactivation occurred following HDAC inhibition. In conclusion, these studies provide significant insights to gammaherpesreactivation that may occur in vivo via pathogen-pathogen interaction

Variation of theanine, phenolic, and methylxanthine compounds in 21 cultivars of Camellia sinensis harvested in different seasons

This is the first study to use chemometric methods to differentiate among 21 cultivars of Camellia sinensis from China and between leaves harvested at different times of the year using 30 compounds implicated in the taste and quality of tea. Unique patterns of catechin derivatives were observed among cultivars and across harvest seasons. C. sinensis var. pubilimba (You 510) differed from the cultivars of C. sinensis var. sinensis, with higher levels of theobromine, (+)-catechin, gallocatechin, gallocatechin gallate and theasinensin B, and lower levels of (−)-epicatechin, (−)-epigallocatechin (EGC) and (-)-epigallocatechin gallate (EGCG), respectively. Three cultivars of C. sinensis var. sinensis, Fuyun 7, Qiancha 7 and Zijuan contained significantly more caffeoylquinic acids than others cultivars. A Linear Discriminant Analysis model based on the abundance of 12 compounds was able to discriminate amongst all 21 tea cultivars. Harvest time impacted the abundance of EGC, theanine and afzelechin gallate